The compound of formula (I):
(which is hereinafter referred to as the “compound of formula (I)” or the “free base”), is a proprietary cancer agent with a novel mechanism of action, inhibiting Class I phosphatidylinositol-3-kinases (PI3Ks). This class of kinases is an attractive target since PI3Ks play a central role in the transduction of cellular signals from surface receptors for survival and proliferation. The compound of formula (I) exhibits a broad spectrum of activity against tumours of multiple histologic types, both in vitro and in vivo.
Said compound of formula (I) may be synthesised according to the methods given in international patent application PCT/EP2003/010377, published as WO 04/029055 A1 on Apr. 8, 2004, (which is incorporated herein by reference in its entirety), on pp. 26 et seq.
Moreover, said compound of formula (I) is published in international patent application PCT/US2007/024985, published as WO 2008/070150 A1 on Jun. 12, 2008, (which is incorporated herein by reference in its entirety), as the compound of Example 13: 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide. Further, said compound of formula (I) is, in WO 2008/070150, described on pp. 9 et seq., and may be synthesized according to the methods given therein on pp. 42 et seq. Biological test data for said compound of formula (I) is given therein on pp. 101 to 107.
Said compound of formula (I) may exist in one or more tautomeric forms: tautomers, sometimes referred to as proton-shift tautomers, are two or more compounds that are related by the migration of a hydrogen atom accompanied by the migration of one or more single bonds and one or more adjacent double bonds.
The compound of formula (I) may for example exist in tautomeric form (Ia), tautomeric form (Ib), or tautomeric form (Ic), or may exist as a mixture of any of these forms, as depicted below. It is intended that all such tautomeric forms are included within the scope of the present invention.

Said compound of formula (I) may exist as a solvate: a solvate for the purpose of this invention is a complex of a solvent and a compound of formula (I) in the solid state. Exemplary solvates include, but are not limited to, complexes of a compound of the invention with ethanol or methanol.
Said compound of formula (I) may exist as a hydrate: Hydrates are a specific form of solvate wherein the solvent is water.
Technical Problem to be Solved:
In general, for a given pharmaceutically active compound, pharmaceutically acceptable forms of said given pharmaceutically active compound are desired, with the view to increasing the pharmaceutical effectiveness of said pharmaceutically active compound, e.g. improving physical chemical characteristics, such as chemical stability, physical stability, solubility in vivo, improving absorption of the pharmaceutically active compound in vivo, etc. In addition, a drug substance would ideally come in a stable crystal form that can be produced in a reliable way. Amorphous or crystal forms of low order (e.g. mesomorphic forms) are less attractive as they carry the risk of a later form change and changes of physical properties.
However, said compound of formula (I) (which is a free base) could only be prepared in a mesomorphic form that is stable in solid form, but unstable at 70° C. in acidic aqueous solution and carries the above mentioned risk of a later form change.
The formation of a crystalline salt form of the free base (I) might solve the above mention problem once the properties of this form are advantageous with respect to the properties of the free base (I). In our efforts to prepare crystalline salt forms of (I) we experienced that preparing crystalline salt forms of (I) is not as easy as one might expect for a compound carrying basic centers.
Furthermore, the compound of formula (I) exhibits very low solubility in water and most organic solvents. With two very basic centres (Table I, vide infra), solubility is strongly improved in acidic media. Consequently, purification of and final processing of the compound of formula (I) is a challenging task.
The following structure shows the compound of formula (I), on which calculated pKa values have been given in parentheses.

TABLE IpKa values of the compound of formula (I):funct. group/pKa valuesexperimentalcalculatedpKa (Imidazolinoamindine)—10.1pKa (Morpholine)—7.43-7.5 pKa (Aminopyrimidine)—1.99-2.11
More particularly, with regard to the unique chemical structure of the compound of formula (I), vide supra, the physical properties of the compound of formula (I) are not only challenging with regard to the chemical process, the handling of the drug substance and the production of drug product, but additionally offer significant challenges for the development of a stable and reliable HPLC method as well.
It would be desirable to have a pharmaceutically acceptable and crystalline form of the compound of formula (I) which allows its reliable purification, e.g., by crystallization, in view of the difficult, specific technical problems and very low aqueous solubility, and which is easy to handle (e.g., which is a free-flowing solid).
Solution to the Technical Problem:
Various attempts were made to prepare crystalline salts of the compound of formula (I). The formation of crystalline salt forms proved to be difficult, as in general no solution was achieved and in several cases gum-like, sticky materials were formed.
Unexpectedly, and this represents a basis of the present invention, it has been discovered that the dihydrochloride salt of the compound of formula (I), of the present invention (no specific disclosure of which is known to the Applicant's knowledge in the prior art), possesses technically advantageous properties, as seen inter alia in the Experimental Section and Conclusion Section of this text.
The present invention thus relates:                to 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride salt of formula (II):        
or a tautomer, solvate or hydrate thereof,
(which is hereinafter referred to as “the salt of the present invention” or the “dihydrochloride salt”);                to methods of preparing said salt of the present invention;        to said salt of the present invention for the treatment and/or prophylaxis of a disease;        to the use of said salt of the present invention for the preparation of a medicament for the treatment and/or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, more particularly for the treatment or prophylaxis of a cancer, in particular non-small cell lung carcinoma, colorectal cancer, melanoma, pancreatic cancer, hepatocyte carcinoma or breast cancer;        to a pharmaceutical composition comprising said salt of the present invention; and        to a pharmaceutical combination comprising said salt of the present invention in combination with one or more further pharmaceutical agents.        
Methods of preparing the salt of the present invention
The present invention also relates to a method of preparing the dihydrochloride salt of formula (II) of the present invention, which involves the addition of hydrochloric acid to the compound of formula (I), or, inversely, the addition of the compound of formula (I) to hydrochloric acid.
In accordance with an embodiment of the present invention, said method of preparing the dihydrochloride salt of formula (II) of the present invention comprises adding hydrochloric acid to a compound of formula (I):
preferably in suspension,
thereby forming said dihydrochloride salt of formula (II):

In accordance with an embodiment of the present invention, said method of preparing the dihydrochloride salt of formula (II) of the present invention comprises:                a) adding hydrochloric acid, such as aqueous hydrochloric acid solution (32%) for example, to a suspension of said compound of formula (I) in a medium, such as water for example, at a temperature of between the freezing point of the mixture and the boiling point of the mixture, such as at a temperature of 20° C.). (+−2°), until a pH of 3 to 4 is reached;        b) stirring the resulting mixture at a temperature of between the freezing point of the mixture and the boiling point of the mixture, such as at room temperature for example, for a period of time, such as for more than 10 minutes for example; and, optionally        c) filtering off the resulting solid and washing the filtercake, such as with water for example, then adjusting the pH of the filtrate to pH 1.8 to 2.0 using hydrochloric acid, such as aqueous hydrochloric acid solution (32%) for example; and, optionally,        d) stirring the mixture for a period of time, such as 10 minutes for example, at a temperature between the freezing point and the boiling point of the mixture, such as at room temperature for example, adding ethanol, followed by further stirring for a period of time, such as for 10 minutes for example; and, optionally,        e) adding seed crystals, optionally followed by adding ethanol over a period of time such as within 5 hours for example; and, optionally,        f) filtering off the resulting dihydrochloride of formula (II), optionally washing with a water-ethanol mixture and optionally drying, such as in vacuo for example,thus providing the dihydrochloride salt of formula (II) of the present invention.        
In accordance with an embodiment of the present invention, said method of preparing the dihydrochloride salt of formula (II) of the present invention comprises:                a) adding said hydrochloric acid to said compound of formula (I) in acetone/water or ethanol/water for example; and, then, optionally,        b) heating at a temperature between the boiling point and the freezing point of the mixture, such as at 40 to 60° C. for example, such as at 50° C. for example, for a period of time preferably of 0, 2 to 2 hours for example, such as for 0.5 hours for example; then, optionally,        c) heating further at a temperature between the boiling point and the freezing point of the mixture, such as at 30 to 40° C. for example, such as at 35° C. for example, for a period of time such as 1 to 4 hours for example, with optional stirring of said suspension at a temperature of between the boiling point and the freezing point of the mixture, such as 10 to 45° C. for example, such as at 35° C. for example, for a period of time preferably 12 to 72 hours for example, such as for 72 hours for example, optionally followed by stirring said suspension at a temperature of between the freezing point of the mixture and the boiling point of the mixture, such as at room temperature for example, for a period of time of 0 to 4 hours, such as 2 hours for example; and, optionally,        d) filtering, optional washing and drying,thus providing the dihydrochloride salt of formula (II) of the present invention.        
In accordance with an embodiment of the present invention, said method of preparing the dihydrochloride salt of formula (II) of the present invention is as follows:                said hydrochloric acid is concentrated aqueous hydrochloric acid solution (1.33 g, 36% HCl) and is added to said compound of formula (I) in an acetone/water mixture (50 mL, 8:2 v/v), followed by heating at a temperature of 50° C., for a period of time of 0.5 hours, then followed by further heating, at a temperature of 35° C., for a period of time of 72 hours, then with stirring of said suspension at a temperature of room temperature, for a period of time of 2 hours, followed by filtration, washing with an acetone/water mixture, and drying in a vacuum oven (40° C., 100 mbar, 16 h), thus providing said dihydrochloride salt of formula (II) of the present invention.        